EcDNA
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB50518 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR8264078.fastq.gz | Fastqsanger.gz | |||
| ERR8264079.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 2 of 2 |
Similar Datasets
Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
2020-11-25 | GSE159972 | GEO
Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
2021-05-24 | GSE175452 | GEO
Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
2021-05-24 | GSE175451 | GEO
Project description:Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. EcDNA renders tumours treatment-resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival. At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses of ecDNA transcription reveal pervasive RNA transcription and associated single-stranded DNA (ssDNA), leading to excessive transcription replication conflicts and replication stress (RS) compared to chromosomal loci. Nucleotide incorporation on ecDNA is markedly slower, and RS is significantly higher in ecDNA-containing tumours regardless of cancer type or oncogene cargo. pRPA2-S33, a mediator of DNA damage repair that binds ssDNA, shows elevated localization on ecDNA in a transcription dependent manner, along with increased DNA double strand breaks, and activation of the S-phase checkpoint kinase, CHK1. Genetic or pharmacological CHK1 inhibition abrogates the DNA replication check point, causing extensive and preferential tumour cell death in ecDNA-containing tumours. We advance a highly selective, potent, and bioavailable oral CHK1 inhibitor, BBI-2779, that preferentially kills ecDNA-containing tumour cells. In a gastric cancer model containing FGFR2 on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer. This work was delivered as part of the eDyNAmiC team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK (CGCATF-2021/100012 and CGCATF-2021/100025) and the National Cancer Institute (OT2CA278688 and OT2CA278635) to H.Y.C., P.S.M., and V.B. This project was supported by NIH RM1-HG007735 (H.Y.C., W.J.G., C.C.).
2024-05-23 | GSE249654 | GEO
Project description:In this study, we established ecDNA-containing cell models by either transfecting synthetic circular DNA or excising endogenous chromosomal DNA. We found that ecDNA can be stable maintained in these cell models. By identifying proteins on nascent DNA, we found DNA damage repair pathway was significantly enriched in ecDNA-containing cells. ecDNA can activate DNA damage response. Further evidence show that TOP2B and LIG3. The association of ecDNA replication with cell proliferation and DNA damage response was explored by comprehensive profiling and analysis. Utilizing EdU (5-ethynyl-2’-deoxyuridine)-immunoprecipitation-mass spectrometry (EdU-IP-MS), we identified critical regulators involved in ecDNA replication and examined their functional roles in cancer cell DNA damage response and proliferation.
2025-04-18 | PXD060725 | Pride
Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
2020-11-25 | GSE159985 | GEO
Project description:Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. EcDNA renders tumours treatment-resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival. At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses of ecDNA transcription reveal pervasive RNA transcription and associated single-stranded DNA (ssDNA), leading to excessive transcription replication conflicts and replication stress (RS) compared to chromosomal loci. Nucleotide incorporation on ecDNA is markedly slower, and RS is significantly higher in ecDNA-containing tumours regardless of cancer type or oncogene cargo. pRPA2-S33, a mediator of DNA damage repair that binds ssDNA, shows elevated localization on ecDNA in a transcription dependent manner, along with increased DNA double strand breaks, and activation of the S-phase checkpoint kinase, CHK1. Genetic or pharmacological CHK1 inhibition abrogates the DNA replication check point, causing extensive and preferential tumour cell death in ecDNA-containing tumours. We advance a highly selective, potent, and bioavailable oral CHK1 inhibitor, BBI-2779, that preferentially kills ecDNA-containing tumour cells. In a gastric cancer model containing FGFR2 on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer. This SuperSeries is composed of the SubSeries listed below. This work was delivered as part of the eDyNAmiC team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK (CGCATF-2021/100012 and CGCATF-2021/100025) and the National Cancer Institute (OT2CA278688 and OT2CA278635) to H.Y.C., P.S.M., and V.B. This project was supported by NIH RM1-HG007735 (H.Y.C., W.J.G., C.C.).
2024-05-23 | GSE249657 | GEO
Project description:Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high oncogene expression through gene amplification and altered gene regulation. Gene induction typically involves cis regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs, clusters of ~10-100 ecDNAs within the nucleus, enable intermolecular enhancer-gene interactions to promote oncogene overexpression in trans. ecDNAs encoding multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumors. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the BET protein BRD4 in a MYC-amplified colorectal cancer cell line. BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-based oncogene transcription. A BRD4-bound promoter in PVT1 is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent MYC expression. PVT1 promoter on a heterologous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic CRISPRi silencing of ecDNA enhancers reveal intermolecular enhancer-gene activation among multiple oncogene loci amplified on distinct ecDNAs. Together, these results demonstrate that ecDNA hubs are protein-tethered clusters of ecDNAs which enable intermolecular transcriptional regulation. ecDNA hubs may act as units of oncogene function, cooperative evolution, and potential targets for cancer therapy.
2021-09-22 | GSE184566 | GEO
Project description:Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. EcDNA renders tumours treatment-resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival. At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses of ecDNA transcription reveal pervasive RNA transcription and associated single-stranded DNA (ssDNA), leading to excessive transcription replication conflicts and replication stress (RS) compared to chromosomal loci. Nucleotide incorporation on ecDNA is markedly slower, and RS is significantly higher in ecDNA-containing tumours regardless of cancer type or oncogene cargo. pRPA2-S33, a mediator of DNA damage repair that binds ssDNA, shows elevated localization on ecDNA in a transcription dependent manner, along with increased DNA double strand breaks, and activation of the S-phase checkpoint kinase, CHK1. Genetic or pharmacological CHK1 inhibition abrogates the DNA replication check point, causing extensive and preferential tumour cell death in ecDNA-containing tumours. We advance a highly selective, potent, and bioavailable oral CHK1 inhibitor, BBI-2779, that preferentially kills ecDNA-containing tumour cells. In a gastric cancer model containing FGFR2 on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer. This work was delivered as part of the eDyNAmiC team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK (CGCATF-2021/100012 and CGCATF-2021/100025) and the National Cancer Institute (OT2CA278688 and OT2CA278635) to H.Y.C., P.S.M., and V.B. This project was supported by NIH RM1-HG007735 (H.Y.C., W.J.G., C.C.).
2024-05-23 | GSE267235 | GEO
Project description:Extrachromosomal DNA (ecDNA) are circular DNA bodies that play critical roles in tumor progression and treatment resistance by amplifying oncogenes across a wide range of cancer types. ecDNA lack centromeres and are thus not constrained by typical Mendelian segregation, enabling their unequal accumulation within daughter cells and associated increases in copy number. Despite intrinsic links to their oncogenic potential, the fidelity and mechanisms of ecDNA inheritance are poorly understood. Here, we show that ecDNA are protected against cytosolic mis-segregation through mitotic clustering and by tethering to mitotic chromosome ends. High fidelity nuclear segregation of MYC-amplifying ecDNA depends on BRD4 transcriptional co-activation and mitotic transcription of the long non-coding RNA PVT1, which is co-amplified with MYC in colorectal and prostate cancer cell lines. Disruption of ecDNA mitotic clustering through BRD4 inhibition, PVT1 depletion, or inhibiting mitotic transcription results in cytosolic mis-segregation, ecDNA chromosomal reintegration, and the formation of homogeneously staining regions (HSRs). We propose that nuclear inheritance of ecDNA is facilitated by an RNA-based mechanism that clusters ecDNA during mitosis and protects against cytosolic missegregation and chromosomal reintegration.
2025-07-03 | GSE299272 | GEO